Abstract
In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that TfAP-2 and Twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2β and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2β and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2β and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2β may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.
Highlights
The human genes TFAP2B and KCTD15 were strongly linked to obesity in multiple genome-wide association studies (GWAS) [1,2,3,4], though it is still not understood how they regulate obesity
This function may be conserved in mammals, as we discovered that mouse AP-2b and Kctd15 proteins directly interact in a mouse hypothalamic cell line and co-localize in areas of the mouse brain involved in modulating feeding behavior
Our study describes how the obesity-linked homologues TfAP-2 and Tiwaz regulate a unique feedback system involving noradrenalin-like octopamine and the CCK homolog Dsk, that exert positive and negative effects on Drosophila feeding behavior
Summary
The human genes TFAP2B (encoding AP-2b) and KCTD15 were strongly linked to obesity in multiple genome-wide association studies (GWAS) [1,2,3,4], though it is still not understood how they regulate obesity. In the fruit fly Drosophila melanogaster, TFAP2B and KCTD15 are both highly conserved, encoded by TfAP-2 and Tiwaz (Twz), respectively [5,6,7]. It was shown in zebrafish embryos that Kctd interacts directly with AP-2a (Tfap2a) to inhibit AP-2a function, and in Drosophila there is evidence for an association between TfAP-2 and Twz [6,8,9]. TfAP-2 and Twz had a strong interaction in a large scale yeast two-hybrid screen using almost the entire Drosophila proteome [9]. We have shown in adult males that TfAP-2 and Twz genetically interact to control aggressive behavior by regulating octopamine production and secretion, which in turn regulates the expression of the Drosophila cholecystokinin (CCK) homolog Drosulfakinin (Dsk) [6]. We demonstrated that overexpression of Dsk was sufficient to induce aggressive behavior in males
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